Low-Dose Infigratinib Increases Bone Growth And Corrects Growth Plate Abnormalities In An Achondroplasia Mouse Model
© The Author(s) [2024]. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research..
Achondroplasia, the most common form of disproportionate short stature, is caused by gain-of-function point mutations in fibroblast growth factor receptor 3 (FGFR3). Abnormally elevated activation of FGFR3 modulates chondrocyte proliferation and differentiation via multiple signaling pathways, such as the MAPK pathway. Using a mouse model mimicking achondroplasia (Fgfr3Y367C/+), we have previously shown that daily treatment with infigratinib (BGJ398), a selective and orally bioavailable FGFR1-3 inhibitor, at a dose of 2 mg/kg, significantly increased bone growth. In this study, we investigated the activity of infigratinib administered at substantially lower doses (0.2 and 0.5 mg/kg, given once daily) and using an intermittent dosing regimen (1 mg/kg every 3 days). Following a 15-day treatment period, these low dosages were sufficient to observe significant improvement of clinical hallmarks of achondroplasia such as growth of the axial and appendicular skeleton and skull development. Immunohistological labeling demonstrated the positive impact of infigratinib on chondrocyte differentiation in the cartilage growth plate and the cartilage end plate of the vertebrae. Macroscopic and microcomputed analyses showed enlargement of the foramen magnum area at the skull base, thus improving foramen magnum stenosis, a well-recognized complication in achondroplasia. No changes in FGF23 or phosphorus levels were observed, indicating that the treatment did not modify phosphate homeostasis. This proof-of-concept study demonstrates that infigratinib administered at low doses has the potential to be a safe and effective therapeutic option for children with achondroplasia.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research - (2024) vom: 09. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Demuynck, Benoit [VerfasserIn] |
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| Links: |
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| Themen: |
ACHONDROPLASIA |
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| Anmerkungen: |
Date Revised 09.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1093/jbmr/zjae051 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370796152 |
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| 520 | |a Achondroplasia, the most common form of disproportionate short stature, is caused by gain-of-function point mutations in fibroblast growth factor receptor 3 (FGFR3). Abnormally elevated activation of FGFR3 modulates chondrocyte proliferation and differentiation via multiple signaling pathways, such as the MAPK pathway. Using a mouse model mimicking achondroplasia (Fgfr3Y367C/+), we have previously shown that daily treatment with infigratinib (BGJ398), a selective and orally bioavailable FGFR1-3 inhibitor, at a dose of 2 mg/kg, significantly increased bone growth. In this study, we investigated the activity of infigratinib administered at substantially lower doses (0.2 and 0.5 mg/kg, given once daily) and using an intermittent dosing regimen (1 mg/kg every 3 days). Following a 15-day treatment period, these low dosages were sufficient to observe significant improvement of clinical hallmarks of achondroplasia such as growth of the axial and appendicular skeleton and skull development. Immunohistological labeling demonstrated the positive impact of infigratinib on chondrocyte differentiation in the cartilage growth plate and the cartilage end plate of the vertebrae. Macroscopic and microcomputed analyses showed enlargement of the foramen magnum area at the skull base, thus improving foramen magnum stenosis, a well-recognized complication in achondroplasia. No changes in FGF23 or phosphorus levels were observed, indicating that the treatment did not modify phosphate homeostasis. This proof-of-concept study demonstrates that infigratinib administered at low doses has the potential to be a safe and effective therapeutic option for children with achondroplasia | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ACHONDROPLASIA | |
| 650 | 4 | |a FGFR3 | |
| 650 | 4 | |a INFIGRATINIB LOW DOSE | |
| 650 | 4 | |a MOUSE MODEL | |
| 650 | 4 | |a PRECLINICAL STUDY | |
| 700 | 1 | |a Flipo, Justine |e verfasserin |4 aut | |
| 700 | 1 | |a Kaci, Nabil |e verfasserin |4 aut | |
| 700 | 1 | |a Dambkowski, Carl |e verfasserin |4 aut | |
| 700 | 1 | |a Paull, Morgan |e verfasserin |4 aut | |
| 700 | 1 | |a Muslimova, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Bhavik P |e verfasserin |4 aut | |
| 700 | 1 | |a Legeai-Mallet, Laurence |e verfasserin |4 aut | |
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